Ideal chemotherapeutic drugs against cancer would target and eradicate malignant cells while leaving normal cells intact, thus minimizing unwanted side effects of the treatment. Current drug therapy for cancer generally involves administering a cancer chemotherapeutic agent systemically, and affects both cancerous and normal cells. Recent developments in targeted therapies include monoclonal antibodies against growth factor receptors expressed on tumors to prevent cancer progression. While these target specific antibody drugs bring higher hopes for better disease management, only a small number of selected patients benefit from these treatments. This is because not all patients express the target proteins at high enough levels in tumors for the therapies to be effective.
Hyaluronan (HA) is a glycosaminoglycan found in all vertebrate tissues and body fluids. HA is composed of repeating N-acetyl-D-glucosamine and D-glucuronate disaccharide units, and its molecular weight ranges from 106 to 107. HA is synthesized by HA synthases (Has-1, Has-2, and Has-3 in humans), and the turnover rate in the body is high—less than 5 min in the blood, 1-2 days in the skin, and 1-3 weeks in cartilage. HA is digested by hyaluronidases (Hyals) that are found in circulating blood and tissues, and digested HA fragments can act as signaling molecules—high molecular weight HA can trigger anti-angiogenic and anti-inflammatory responses and low molecular weight HA (˜20 kDa) can induce cytokine synthesis, whereas lower molecular weight HA (<20 kDa) can activate dendritic cells and antigen-presenting cells.
The altered regulation of HA seems to be important in tumor invasiveness, migration, and progression. Elevated levels of HA are found in various malignant tumors, including melanoma, and cancers of ovaries, breast, lung, and bladder. In breast and ovarian cancers, high HA levels are associated with poor patient survival. In addition, anchorage-independent growth and tumorigenicity were observed in hyaluronan synthase 2 (HAS-2) gene transfected human fibrosarcoma cells, which was correlated with overproduction of HA.
There is a need in the art for cancer treatments that provide for more targeted delivery of a therapeutic agent to a tumor. The present invention addresses this need; and provides related advantages.
Literature
U.S. Pat. Nos. 5,800,811, 660,843, and 6,686,179; U.S. Patent Publication Nos. 20050033026 and 20040234497.